2-dihalo lower alkyl-4-phenyl-quinazoline 3-oxide



United States Patent Int. Cl. C07d 53/06 US. Cl. 260-251 7 ClaimsABSTRACT OF THE DISCLOSURE Novel 2 -dihalo loweralkyl-4-phenylquinazoline 3-oxides A and their conversion into3-halo-1,4-benzodiazepin- 2-one 4-oxides B. B can be converted intoknown pharmacologically valuable 1,4-benzodiazepin-2-ones C. C aremuscle relaxant, sedative and anti-convulsant agents.

RELATED APPLICATION This application is a division of Ser. No. 326,372filed November 27, 1963 in the names of Arthur Stempel and Leo HenrykSternbach, now US. Patent No. 3,321,467. The benefit 0f the elfectivedate of this prior, pending application is hereby claimed.

BRIEF SUMMARY OF .THE INVENTION The invention relates to Z-dihalo loweralkyl-4-phenylquinazoline 3-oxides and to their conversion into compounds which can be characterized broadly in a chemical sense as being3-halo-1,4-benzodiazepin-2-one 4-oxides. Furthermore, the invention, inanother of its aspects, relates to novel processes for preparing certainend products utilizing such chemical compounds as are characterizedbroadly hereinabove, known prior to the invention and useful asmedicinal agents by virtue of their pharmacological activity.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds characterizedbroadly above as being 3-halo-1,4-benzodiazepin-2-one 4-oxides are ofthe formula wherein R and R are selected from the group consisting ofhydrogen, halogen, nitro, trifluoromethyl and lower alkyl;

R is selected from the group consisting of hydrogen and lower alkyl andX is halogen.

In a preferred aspect, R in Formula I above is hydrogen.

The novel chemical compounds of Formula I can be prepared by severaldifferent procedures. Such procedures are illustrated graphically in thefollowing diagrammatical flow sheet wherein the symbols R R R and X havethe same meaning ascribed thereto hereinabove and Y is selected from thegroup consisting of chlorine and bromine. In a preferred aspect, X isselected from the group consisting of fluorine, bromine and chlorine,most advantageously, chlorine.

As is evident from the diagrammatical flow sheet, each of thepreparative procedures illustrated involves, in its first stage,acylating the 11- or the B-oxime of Formula II above with an a,a-dihalolower acyl halide (compounds having the formula X CRCOY above), Suitable0:,ot-dihalo lower acyl halides are represented by dichloroacetylchloride, dibromoacetyl chloride and a,a-dibromopropionyl chloride andthe like. The halogen atoms of the dihalo moiety can be identical ordiiferent and are preferably, as noted above, selected from the groupconsisting of chlorine, bromine or fluorine, advantageously, chlorine.The product resulting from the ensuing reaction is either a novel uor anovel B-a,a-dihaloacyl ortho-amino benzophenone oxime (compounds ofFormula HI and Formula 1V above) depending upon whether the aor the3-oxime of the Formula II above is employed as the starting material.This reaction is advantageously effected in the presence of any suitablebase which may be, for

example, an alkali metal hydroxide such as sodium hydroxide, an alkalineearth metal hydroxide such as calcium or barium hydroxide and an organicbase such as pyridine. An alkali metal hydroxide, e.g. sodium hydroxide,is preferably employed due to the ready availability thereof.

In preparing compounds corresponding to Formula I above, compoundshaving the Formula III above (a,adihaloacyl oximes a-form) and compoundshaving the Formula IV above (a,u-dihaloacyl oximes St-form) are treatedwith acid agents such as strong mineral acids, for example, hydr-ohalicacids, e.g. hydrochloric acid, sulfuric acid, phosphoric acid and thelike whereby dehydration and ring closure to the quinazoline of FormulaV above occurs. Similarly, the dehydration and ring closure can beeffected in the presence of boron triftuoride. However, thelast-mentioned procedure does not constitute part of the presentinvention. Compounds corresponding to Formula V above are novelcompounds and, thus, constitute part of the present invention.

Conversion of compounds of Formula V above to the desired compounds ofFormula I above as illustrated is effected by treating compounds ofFormula V with a suitable inorganic base such as an alkali metalhydroxide, e.g. sodium hydroxide or an alkaline earth metal hydroxide,e.g. calcium hydroxide, advantageously in an inert organic solvent whichmay be a lower alkanol, for example, ethanol, acetone, a di-loweralkyloxy alkane such as dimethoxyethane or an ether such as dioxane. Bythis treatment, the quinazoline ring is converted into a 3-ha1o-l,4-benzodiazepin-Z-one 4-oxide (compounds of Formula I above).

An alternate procedure for the preparation of compounds of Formula Iabove involves treating compounds of Formula IV above (fi-oximederivatives) with an inorganic base, for example, an alkali metalhydroxide such as sodium hydroxide or an alkaline earth metal hydroxide,such as calcium hydroxide, here again, advantageously, in the presenceof an inert organic solvent of the types exemplified hereinabove inconnection with the conversion of compounds of Formula IV to compoundsof Formula 1.

Compounds of Formula IV can be prepared from compounds of Formula V bytreating the latter with an inorganic base, e.g. an alkali metalhydroxide such as sodium hydroxide or an alkaline earth metal hydroxide.Compounds of Formula IV, prepared thusly, can be further reacted, withor without isolation from the reaction medium in which they areprepared, in the manner set out above to thereby form the correspondingcompounds of Formula I above.

As is noted above, the invention, in one of its aspects, relates tonovel processes for preparing certain end products known prior to theinvention and which are useful as medicinal agents. Such compounds havethe formula of wherein R R and R are as above; R is selected from thegroup consisting of lower alkyloxy, lower acyloxy, hydroxy and hydrogenand A is selected from the group consisting of and The preparation ofcompounds having the Formula VI above from compounds having the FormulaI above is a novel process aspect of the invention and, broadly stated,involves treating a compound of Formula I above with a conversion meansselected from the group consisting of a conversion means comprising ahydrogenation catalyst and hydrogen and a conversion means comprisingphosphorus trichloride and a compound having the formula of 4 MOR VIIwherein M is selected from the group consisting of hydrogen, alkalimetals and alkaline earth metals and R is selected from the groupconsisting of lower alkyl and lower acyl.

More particularly, one of the embodiments embraced by the said novelprocess aspects of the invention provides a method of making a compoundcorresponding to Formula VI above wherein R is lower alkyloxy and A is=N This preparation is effected by first treating compoundscorresponding to Formula I above with phosphorous trichloride and,thereafter, with a compound having the Formula VII above (MOR wherein Mis hydrogen and R is lower alkyl, e.g. a lower alkanol such as ethanol,propanol and the like.

Compounds corresponding to Formula VI above wherein R lower acyloxy andA is =N can be prepared by initially treating compounds of the Formula Iabove with phosphorous trichloride and, thereafter, with a compound ofFormula VII above (MOR wherein M is selected from the group consistingof alkali metals and alkaline earth metals and R is lower acyl.Preferably, in this embodiment, M in Formula VII above is sodium, andthe lower acyl moiety of compounds of Formula VII above is acetyl. Thecompound so obtained can be hydrolyzed employing any convenienthydrolyzing techniques such as treatment with a base in a solvent, e.g.a lower alcoholic solution, e.g. methanolic of sodium hydroxide tothereby form compounds of Formula VI above wherein R is hydroxy and A isCompounds of Formula VI above wherein R is hydrogen and A is =N andcompounds of the Formula VI above wherein R is hydrogen and A is canalso be prepared from compounds of formula I above by hydrogenating thelatter employing any suitable hydrogenating procedure, for example,hydrogenating in the presence of a hydrogenation catalyst such as Raneynickel, palladium and the like.

The term lower alkyl, as used throughout the disclosure, comprehendsboth straight and branched chain hydrocarbon groups such as methyl,ethyl, n-propyl, isopropyl, butyl and the like. The term halogen, asused throughout the disclosure, is intended to encompass all the fourforms thereof, i.e. chorine, bromide, fluorine and iodine. Chlorine,bromine and fluorine are preferred. The expression lower acyl refers toacyl groups which may be straight or branched chain such as acetyl, andthe term a-dihalo-lower acyl connotes an acyl group bearing dihalogensubstitutents on the u-carbon atom, e.g. groups such dichloroacetyl,dibromoacetyl, 06,0t-dlbI'OD10- propinonyl and the like.

The foregoing is a general description of the main synthetic routes forthe preparation of 3-halo-l,4-benzodiazepine 4-oxides and to theprocesses utilizing such compounds in the preparation of certain endproducts useful as medicinal agents. It will be readily apparent to oneskilled in the art that variations of these procedures are possible.

The following examples are illustrative but not limitative of thecompounds of this invention and the procedures for their preparation.All temperatures stated are in degrees centigrade.

Example 1 To a solution of 100 g. (0.406 mole) of 2-amino-5-chlorobenzophenone oxime (oz-form) in 2 1. of ether, 500 ml. of waterwas added and the stirred mixture cooled in an ice bath to 5. Then 44ml. (67.3 g., 0.455 mol) of dichloroacetyl chloride was added slowlymaintaining the temperature below +10 and keeping the reaction slightlyalkaline by the simultaneous addition of 10 percent sodium hydroxide.The mixture was stirred for 30 minutes in the cold after all of thedichloroacetyl chloride had been added. The ether layer was thenseparated, washed twice with .500 ml. portions of cold water and driedover sodium sulfate. Most. of the solvent was distilled off atatmospheric pressure and 100 ml. of benzene was added to the residue.The solvent was evaporated in vacuo to remove any water that remained.The residue was crystallized from benzene to give the oxime of2'-benzoyl-2,2,4'- trichloroacetanilide (ct-form), melting at l34l36.

Example 2 A solution of 98 g. of the oxime of 2'-benzoyl-2,2,4'-trichloroacetanilide (a-form) in 1 l. of acetic acid was heated on asteam bath for 1 /2 hours while hydrogen chloride was bubbled throughthe solution. The reaction mixture was kept at room temperature for 16hours and then concentrated to dryness in vacuo. The residue thusobtained was dissolved in methylene chloride and washed with dilutesodium bicarbonate and water. After drying over sodium sulfate, thesolvent was distilled off. On stirring with ether, the residuecrystallized to give 29 g. of crude6-chloro-2-dichloromethyl-4-phenylquinazoline 3-oxide, melting at105-135 The crude product was purified by dissolving it in methylenechloride and passing it through a column of 250 g. of neutral alumina.Elution with methylene chloride gave a fraction which was recrystallizedfrom a mixture of methylene chloride and hexane to give a purified formof the product melting at 153-154.

Example 3 A solution of 15 ml. of 2 N sodium hydroxide in 100 ml. of1,2-dimethoxyethane was chilled to -5 and 5.0 g. (14.7 mmoles) of6-chloro-2-dichloromethyl-4-phenylquinazoline 3-oxide were added. After30 minutes at this temperature, 100 ml. of water was added slowly,keeping the temperature below 10, Then, 3 N hydrochloric acid was addeddropwise until the solution was neutral. The crystalline product wasfiltered off, washed with water and dried over phosphorus pentoxide invacuum to give 3,7-dichloro-l,3-dihydro -phenyl-2H 1,4 benzodia-Zepin-Z-one 4-oxide, melting at 194195 dec. Recrystallization from amixture of tetrahydrofuran and hexane gave colorless needles melting at2l0-21 1 Example 4 To a solution of 100 g. (0.406 mole) of Z-aminQ-S-chlorobenzophenone oxime (,B-form) in 2 l. of ether, 500 ml. of waterwas added and the stirred mixture cooled in an ice bath to 5. Then 44ml. (67.3 g., 0.455 mole) of dichloroacetyl chloride was added slowlymaintaining the temperature below and keeping the reaction slightlyalkaline by the simultaneous addition of 10 percent sodium hydroxide.The mixture was stirred for 30 minutes in the cold after all of thedichloroacetyl chloride had been added. The ether layer was thenseparated, washed twice with 500 ml. portions of cold water and driedover sodium sulfate. Most of the solvent was distilled olf atatmospheric pressure and 100 ml. of benzene was added to the residue.The solvent was evaporated in vacuo to remove any water that remained.The residue was crystallized from benzene to give the oxime of2'-benzoyl-2,2,4- trichloroacetanilide (,B-form), melting at 159l60.

Example 5 To a solution of ml. of 2 N sodium hydroxide in 100 ml. ofmethanol cooled to 05, 5.0 g. (14.7 mmoles) of6-chloro-2-dichloromethyl-4-phenylquinazoline 3-oxide were added. After30 minutes, ml. of water were added and the reaction neutralized by theaddition of 3 N hydrochloric acid. The crystalline product was filteredand dried over phosphoric pentoxide in vacuo to give a crude productmelting at 159-160 dec. The residue was added to a mixture oftetrahydrofuran and hexane. A precipitate which formed was filtered off.The mother liquor was concentrated to dryness in vacuo and the residuerecrystallized from a mixture of tetrahydrofuran and hexane. Smallcrystals separated, then large needles began to form. The supernatantliquor was decanted and yielded long needles. After severalcrystallizations from tetrahydrofuran and hexane, the fl-oxime of2-benzoyl- 2,2,4-trichloroacetanilide melting at 160-162 was obtained.

Example 6 A solution of 15 ml. of 2 N sodium hydroxide in 100 ml. of1,2-din1ethoxyethane was cooled to 0-5 and 5.0 g. 14.0 mmoles) of2'-benzoyl-2,2,4'-trichloroacetanilide oxime (B-form) was added. After30 minutes at this temperature, the solution was diluted with 100 ml. ofwater and neutralized by the addition of 3 N hydrochloric acid. Thecrystalline product was filtered off and dried over phosphorus pentoxidein vacuo to give crude 3,7-dichloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide, melting at206-207. Recrystallization from a mixture of tetrahydrofuran and hexanegave colorless needles melting at 210-2l1.

Example 7 A solution of 15 ml. of 2 N sodium hydroxide in 100 ml. of1,2-dimethoxyethane was chilled to 05 and 5.0 g. (14.7 mmoles) of6-chloro-2-dichloromethyl-4-phenylquinazoline 3-oxide was added. Themixture was maintained at this temperature for 30 minutes yielding 3,7-dichloro-1,3-dihydro-5-phenyl-2H-1,4 benzodiazepin 2- one 4-oxide. Then,about 10-25 g. of Raney nickel was added and the mixture hydrogenated atroom temperature and atmospheric pressure. When about 15 mmoles ofhydrogen had been absorbed, the reaction was stopped. The catalyst wasremoved by filtration and the filtrate neutralized by the addition of 3N hydrochloric acid. Most of the solvent was removed by concentration invacuo and the residue was partitioned between methylene chloride andwater. The organic layer was dried over sodium sulfate and concentratedto dryness. The residue was crystallized from a mixture of acetone andhexane to give 7-chloro-1,3-dihydro-5-phenyl 2H 1,4 benzodiazepin-Z-one4-oxide crystallizing as colorless plates melting at 228-230 dec.Recrystallization from ethanol gave a product melting at 234235.

Example 8 The mother liquors obtained in Example 7 were concentrated todryness and the residue crystallized from a mixture of acetone andhexane yielding a precipitate which was separated. This mother liquorwas again taken to dryness and crystallized from ethyl acetate to give7-chloro-1,3-dihydro-5-phenyl-2H 1,4 benzodiazepin- 2-one, melting at207-209. Recrystallization from ethyl acetate gave a product melting at212213.5.

Example 9 To a suspension of 4.7 g. of 3,7-dichloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide in 100 ml. of chloroform, 10ml. of phosphorus trichloride was added. The mixture was stirred andheated to reflux for 30 minutes then concentrated to dryness in vacuo.The residue was partitioned between chloroform and ice cold dilutesodium bicarbonate solution. After drying the organic layer over sodiumsulfate, the solvent was distilled off in vacuo. The residue wasdissolved in 25 ml. of ethanol and the solution refluxed for 5 minutes,then concentrated to dryness in vacuo. The residue was crystallized fromacetonitrile. The so-crystallized residue was then partitioned betweenchloroform and dilute sodium bicarbonate, dried over sodium sulfate andconcentrated to dryness in vacuo. Crystallization of the residue fromacetonitrile gave 7-chloro-1,3-dihydro-3-ethoxy-5-phenyl-2H-1,4-benzodiazepin-2-one, melting at 221-223.

Example 10 A solution of 5.0 g. (15.5 mmoles) of 3,7-dichloro-1,3-dihydro-S-phenyl-ZH-1,4-benzodiazepin-2-one 4-oxide in 100 ml. ofchloroform and 10 ml. of phosphorus trichloride was heated to reflux for30 minutes. The mixture was then concentrated to dryness in vacuo andthe residue partitioned between chloroform and water. The organic layerwas washed with water and dilute sodium bicarbonate and, followingdrying over sodium sulfate, concentrated to dryness in vacuo. The crudeproduct thus obtained was dissolved in 100 ml. of acetic acid containing3.0 g. of anhydrous sodium acetate and the solution heated at 80-90 for10 minutes. Acetic acid was distilled off in vacuo and the residuepartitioned between chloroform and water. The chloroform layer waswashed with water and dilute sodium bicarbonate, dried over sodiumsulfate and the solvent was then distilled off in vacuo. The residue wascrystallized from a mixture of methylene chloride and hexane to give3-acetoxy-7- chloro-1,3-dihydro--phenyl-2H 1,4 benzodiazepin 2- one,melting at 230-236 dec.

Example 11 To a solution of 38 g. (0.15 mole) of the oxime of2-amino-5-nitrobenzophenone in 1 1. of acetic acid containing 13.0 g.(0.15 mole) of sodium acetate, 0.15 mole of dichloroacetyl chloride wasadded slowly at room temperature with stirring. After 2 hours at roomtemperature, the solvent was distilled off in vacuo. The residue thusobtained was partitioned between methylene chloride and water and theorganic layer was then sodium sulfate, the solvent was distilled off"and the resiwashed with sodium bicarbonate. After drying over sodiumsulfate, the solvent was distilled off and the residue crystallized frombenzene to give the oxime of 2- benzoyl-2,2-dichloro-4-nitroacetanilide,melting at 144- 145". Further crystallization gave a product melting at145-146".

Example 1 2 To a warm solution of g. (27.2 mmoles) of the oxime of2'-benzoyl-2,2-dichloro-4-nitroacetanilide in 400 ml. of benzene, 5 ml.of boron trifluoride etherate were added. The mixture was then heated toreflux for 6 hours. During the course of the reaction an oily productseparated. After cooling, the crude reaction mixture was washed withwater and dilute sodium bicarbonate, dried over sodium sulfate andconcentrated to dryness in vacuo. Crystallization of the residue from amixture of tetrahydrofuran and hexane gave 2-dichloromethyl-6-nitro-4-phenylquinazoline 3-oxide crystallizing as yellow needles and meltingat 194-195 and capable of being reacted in the manner set out in Example3 to form 3-chloro-7- nitro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2one 4-oxide.

Example 13 To a stirred solution of 28 g. (0.1 mole) of the a-oxime of2-amino-5-trifluoromethylbenzophenone in 500 ml. of ether, 150 ml. ofwater was added and the mixture chilled to 0-5. Twenty-two ml. (34.6 g.,0.24 mole) of dichloroacetyl chloride was added slowly and,simultaneously, dilute sodium hydroxide was added to keep the reactionslightly alkaline. The reaction mixture was stirred for 30 minutes afterall of the acid chloride was added. The organic layer was thenseparated, washed with water and dried over sodium sulfate. Solvent wasthen distilled off and the residue crystallized from a mixture ofbenzene and hexane to give the oxime of 2-benzoyl-2,2-dichloro-4-trifluoromethyl acetanilide melting at l29-131.

Example 14 To a solution of 10 g. (25.6 mmoles) of the oxime of2-benzoyl-2,2-dichloro-4' trifluoromethylacetanilide in 400 ml. ofbenzene, 5 ml. of boron trifluoride etherate was added and the mixturerefluxed for 5 /2 hours. The solution became turbid after heating forabout 15 minutes. After cooling, the reaction mixture was washed twicewith 250 ml. of water and twice with 250 ml. of a 5 percent aqueoussolution of sodium bicarbonate. The organic layer was dried over sodiumsulfate and the solvent was distilled off in vacuo. On addition of 50ml. of ether to the residue,2-dichloromethyl-4-phenyl-6-trifluorornethylquinazoline 3-oxidecrystallized. The product was found to have a melting point of 162-1641It is capable of be ing reacted in the manner set out in Example 3 toform 3-chloro-7-trifluoromethyl-1,3-dihydro-5-phenyl-2H 1,4-benzodiazepin-Z-one 4-oxide.

Example 15 To a solution of 122 g. (0.34 mole) of the oxime of2-benzoyl2,2,4-trichloroacetanilide (or-form) in 2 l. of benzene atabout 50, 60 ml. of boron trifluoride etherate was added slowly withstirring. The mixture was protected from atmospheric moisture with acalcium sulfate drying tube and heated to reflux. Within a few minutes,white crystals began to appear. After refluxing for 6 hours, thereaction mixture was kept overnight at room temperature. Then, 1 l. ofwater was added with stirring The benzene layer was separated and washedonce with 1 l. of H 0 and then with 2 500 ml. of 5 percent sodiumbicarbonate. The aqueous layers were discarded and the organic phase wasdried over sodium sulfate. Benzene was distilled off in vacuo and theyellow crystalline residue was stirred with 500 ml. of anhydrous etherand then chilled and filtered. It was thereafter dried in a vacuum ovenat 40". This gave 6-chloro-2-dichloromethyl-4- phenylquinazoline3-oxide, melting at 151. Recrystallization from a mixture of methylenechloride and hexane gave yellow plates melting at 153-154.

Example 16 To a solution of 10 g. (2 8 mmoles) of the oxime of2'-benzoyl-2,2,4'-trich1oroacetanilide (fl-form) in 200 ml. of benzeneat 50, there was added 5 ml. of boron trifluoride etherate. The mixturewas then heated to reflux. After about 30 minutes, a solid began tocrystallize. After 5 hours of refluxing, the reaction mixture was cooledto room temperature and stirred with 200 ml. of water. The organic layerwas washed with dilute sodium bicarbonate, dried over sodium sulfate andthe solvent then distilled off in vacuo. The residue crystallized whenstirred with 50 ml. of ether to give6-chloro-2-dichloromethyl-4-phenylquinazoline 3-oxide, melting at147149.

We claim:

1. A compound having the formula of NAO wherein R and R are selectedfrom the group consisting of hydrogen, halogen, nitro, trifluoromethyland lower alkyl; R is selected from the group consisting of hydrogen andlower alkyl; and X is halogen.

2. A compound as defined in claim 1 of the formula6-halo-2-dihalomethyl-4-phenylquinazoline 3-oxide.

3. A compound as defined in claim 1 of the formula6-chloro-2-dichloromethyl-4-phenylquinaz0line 3-oxide.

4. A compound as defined in claim 1 of the formulaZ-dihalomethyl-G-nitro-4-phenylquinazo1ine 3-0xide.

5. A compound as defined in claim 1 of the formulaZ-dichloromethyl-G-nitroA-phenylquinazoline 3-oxide.

6. A compound as defined in claim 1 of the formula 2dihalomethyl-4-phenyl-6-trifluoromethylquinazoline 3- oxide.

7. A compound as defined in claim 1 of the formulaZ-dichloromethyl-4-phenyl-6 trifluoromethylquinazoline 3-0xide.

10 References Cited UNITED STATES PATENTS 2,893,992 7/1959 Sternbach260239 3,120,521 2/1964- Sternbach et al. 260244 3,121,074 2/ 1964Keller et a1. 260239 ALEX MAZEL, Primary Examiner. R. V. RUSH, AssistantExaminer.

US. Cl. X.R. 260-562 232 3 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent NO. Dated July 1,

lnventm-( Arthur Stempel and Leo Henryk Sternbach It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 2, line 15 Acid. Acid should read Acid Agent Column P lines 17-24 in formula IV HHCOCRX2 N1LCOCRX2 C-=NOH should read NOH SIGNED ANDSEALED JUN 3 01970 I Atteat:

Edward M. member, 11-; wmrm E. 50mm, .112.

Anesting Officer C-omissioner of Patents

